Method and paste for articular cartilage transplantation

ABSTRACT

The invention disclosed is a method and material for repairing focal arthritic defects in a mammalian joint, especially in a human knee. The invention disclosed provides an articular cartilage cancellous bone paste in an effective amount for enhancing formation of cartilage. The paste can include a cartilage-stimulating factor.

This is a continuation-in-part of application Ser. No. 08/908,685, filedAug. 7, 1997, now U.S. Pat. No. 5,964,805.

The present invention relates to the field of surgical methods andinstruments for treatment of a focal arthritic defect in a joint of amammal, and more particularly, for treatment of focal arthritic defectsin the knee of a mammal.

REFERENCE TO RELATED APPLICATION

This application is related to U.S. patent application Ser. Nos.08/710,176, 08/797,973 and 08/908,685.

BACKGROUND OF THE INVENTION

Focal arthritic defects are defined as areas of complete hyalinecartilage loss exposing the underlying bone ringed by areas of intacthyaline cartilage. Focal arthritic defects may occur as the result oftrauma or other conditions, such as loss of the protective meniscuscartilage or osteoarthritis. Focal arthritic defects may occur in anyjoint, being especially problematic in the weight-bearing joints, i.e.,in the hip, the knee, and the ankle. Focal arthritic defects in thesejoints lead to pain, swelling, and loss of motion. In the past,treatment of focal arthritic defects has included drilling, abrasion,periosteal covering and bone grafting.

SUMMARY OF THE INVENTION

The present invention provides a surgical technique in which anosteocartilaginous plug, or graft, can be removed from one locationwithin a mammalian joint and moved to another location within the joint,or to another joint, to fill a focal arthritic defect. In oneembodiment, the invention provides a method of repairing an arthriticdefect in a mammalian joint which comprises the steps of forming aroughened, bleeding surface of cancellous bone within the defect;forming a plug of osteocartilaginous tissue from an undamaged sitewithin the joint or from another joint; removing the plug from theundamaged site; crushing and mixing the plug of cartilaginous tissue toform a paste or grout; and inserting the paste into the defect,positioning the paste against the roughened bleeding surface (andoptionally applying an external force to hold the paste in place) for atime sufficient to allow a blood clot to form between said plug and saidroughened bleeding surface.

The invention maybe advantageously performed with an instrument set ofthe type described in U.S. patent application Ser. No. 08/797,973,supplemented with a press, or other device, for crushing the articularcartilage and cancellous bone plug. The instrument set preferablyincludes a coring device and two obturators. The first obturator is usedwith a coring device (or trephine) to harvest articular cartilage andcancellous bone from a site within the intercondylar notch, and thesecond obturator is used with a coring device to transplant theharvested articular cartilage and cancellous bone.

The invention provides the above-referenced paste formed ofosteocartilaginous tissue mixture in an effective amount for enhancingthe formation of cartilage. The paste can include particles of crushedcancellous bone mixed with articular cartilage. Further, the paste caninclude a proteinaceous factor which stimulates the formation ofcartilage.

In one embodiment, the invention provides an articular cartilage pastefor effecting in vivo formation of cartilage. As used herein, the term"for effecting in vivo formation of cartilage" means that the pasteprovides a physical structure to which cartilage-forming cells andundifferentiated mesenchymal cells, and cartilage extracellular matrixcomponents such as collagen fibers and proteoglycans can adhere as wellas the necessary environment to signal cartilage-forming cells toproduce cartilage.

BRIEF DESCRIPTION OF THE DRAWINGS

For a fuller understanding of the nature and the objects of theinvention, reference should be made to the following detaileddescription and the accompanying drawings in which like referencenumerals refer to like elements and in which:

FIG. 1 shows, in perspective view, an instrument set embodying theinvention;

FIG. 2 shows, in sections, the instrument set of FIG. 1; and

FIGS. 3-7 illustrate a method of use of an instrument set embodying theinvention.

DESCRIPTION OF THE PREFERRED EMBODIMENT

The method and/or articular cartilage paste of the invention is suitablefor repairing any arthritic defect in any joint, so long as the defectis not so extensive that no undamaged portion of the joint remains.Preferably, the method and/or paste of the invention is used to repairfocal arthritic defects in the hip. More preferably, the method and/orpaste of the invention is used to repair focal arthritic defects in theankle. Most preferably, the method and/or paste of the invention is usedto repair focal arthritic defects in the knee. Focal arthritic defectsin the joints of any mammal may be repaired in accordance with themethod and/or with the paste of the invention. Preferably, focalarthritic defects in the joints of humans may be repaired using themethod and/or paste of the invention.

For example, when the joint being repaired is a knee, after routinearthroscopic examination has been performed and a focal arthritic defecthas been identified, the procedure is performed as follows, preferablyusing an instrument kit comprising an arthroscopic awl (similar to anice pick), one or more trephines, each with an associated obturator (orplunger) adapted to slide into the central region of its associatedtrephine.

The base of the arthritic defect where the exposed bone is visualizedand then prepared by fracturing with the arthroscopic awl, therebyestablishing a bleeding, roughened bed of cancellous bone. Preferably,the fracture holes are approximately 5-10 mm deep, with an inter-holespacing in the range 1-5 mm, and most preferably 2-3 mm. The blood formsclots over the roughened bed exposed by the fracturing. Attention isnext turned to the intercondylar notch between the two femoral condyles.Within the notch lies the anterior and posterior cruciate ligaments. Thearea anterior to the anterior cruciate ligament on the medial wall ofthe lateral femoral condyle is exposed with a curette, removingoverlying soft tissue. A metal trephine coring device is then manuallybored into the osteocartilaginous surface in that area down into theunderlying cancellous bone to establish and capture anosteocartilaginous graft in the distal tip of the trephine coringdevice. Preferably, the graft is a 1 cm long by 5 mm diametercylindrical plug weighing on the order of 0.25 grams. The trephine isthen backed out of the knee joint. An obturator is introduced into theproximal end of the trephine and advanced to force the graft out of thedistal end of the trephine. The graft is then placed into a graftcrushing device, such as a press, where it is crushed, or morselized, toform a paste-consistency agglomerate (a "tissue paste") of crushedcancellous bone and mixed articular cartilage. The agglomerate is thenloaded into the distal tip of a trephine, which tip is then positionedadjacent to the prepared bed of the arthritic defect. The plunger isintroduced into the proximal end of the trephine and advanced to pushthe agglomerate from the trephine into the defect, where it is held inplace, preferably for a period on the order of three minutes. Duringthat time, blood clots on the roughened bed secure the graft to the bed.The instruments are then removed and the patient kept non weight-bearingfor four weeks.

In one form of the invention, prior to insertion, the osteocartilaginousgraft may be exposed to a proteinaceous factor which stimulates theformation of cartilage. Any cartilage-stimulating factor may be used inthis embodiment, so long as the factor is capable of increasing theamount or rate of formation of cartilaginous tissue within a joint. Forexample, the graft may be exposed to a cartilage-stimulating factorbelonging to the transforming growth factor-β (TGF-β) supergene family.Other cartilage-stimulating factors which can be used in accordance withthe present invention include, but are not limited to, analogs of suchcartilage-stimulating factors having the biological activity of thecorresponding natural cartilage-stimulating factor. Such acartilage-stimulating factor may be in homodimeric or heterodimericform. The cartilage-stimulating factor may be purified from mammaliantissue or it may produced recombinantly from one or more cDNAs encodinga monomer of the cartilage-stimulating factor. The osteocartilaginousgraft can also contain more than one type of cartilage-stimulatingfactor in any combination.

The graft is exposed to and optionally, intermixed with, an effectiveamount of the cartilage-stimulating factor. As used herein, an"effective amount" of cartilage-stimulating factor means the totalamount of cartilage-stimulating factor sufficient to show a meaningfulpatient benefit, i.e., to enhance formation of cartilage in the vicinityof the graft. Preferably, the graft is exposed to and/or intermixed withthe cartilage stimulating factor, such as, for example, acartilage-stimulating factor belonging to the transforming growthfactor-β (TGF-β) supergene family, in an amount ranging from about 0.1ug/ml to about 1.0 ug/ml.

The cartilage-stimulating factor in free form can be administereddirectly to the defect site. Alternatively, the cartilage-stimulatingfactor can be contained within a bioabsorbable and non-toxic carriersuch as a liposome and administered to the defect site. The graft isthen exposed to the cartilage-stimulating factor as thecartilage-stimulating factor elutes from the carrier. The carrier can beselected to release the cartilagestimulating factor at a predeterminedrate to achieve the effective amount of the cartilagegrowth stimulatingfactor to enhance formation of cartilage in the vicinity of the graft.

Further, the cartilage-stimulating factor can be mechanically intermixedwith the paste-like agglomerate form of the graft either aftertransplantation has occurred or preferably, prior to transplantation.The cartilage-stimulating factor can be in its free form or containedwithin a liposome prior to such intermixing.

In another form of the invention, prior to insertion, theosteocartilaginous graft is exposed to and optionally, intermixed with,added cells such as undifferentiated mesenchymal stem cells and/orchondrocytes to enhance formation of cartilage in the vicinity of thegraft. The mesenchymal stem cells can be obtained from blood or bonemarrow. The chondrocytes can be cloned from the patient's own articularcartilage or allograft.

The graft is exposed to and/or intermixed with an effective amount ofthe added cells. Similar to the effective amount ofcartilage-stimulating factor described above, as used herein, an"effective amount" of added cells means the total amount of these cellssufficient to show a meaningful patient benefit, i.e., to enhanceformation of cartilage in the vicinity of the graft. Preferably, thegraft is exposed to and/or intermixed with the added cells in an amountof about 5×10⁶ cells/ml.

The cells can be mechanically intermixed with the paste-like agglomerateform of the graft either prior to transplantation or aftertransplantation has occurred.

Further, a biological glue can be used to fix the paste-like agglomerateform of the graft, the cartilage-stimulating factor and/or themesenchymal and/or other cartilage forming cells to the defect site. Asused herein, the biological glue is an adhesion molecule, or adhesiveportion or analog thereof, which aids in cartilage regeneration byproviding a tacky surface to which cartilage forming cells, cartilagefibers and/or cartilage stimulating factors can stick. The biologicalglue can be administered directly to the defect site. The biologicalglue can also be intermixed with the paste-like agglomerate form of thegraft, the cartilage-stimulating factor and/or the cells either prior totransplantation or after transplantation has occurred. The biologicalglue includes, but is not limited to, fibrin glue; mussel glue, such asmussel glue containing bioadhesive polyphenolic proteins derived fromseveral species of the mussel genus Mytilus (see e.g., U.S. Pat. No.4,585,585); chondronectin; osteonectin; and fibronectin andarginine-glycine-aspartic acid (RGD) peptide (see e.g., U.S. Pat. No.5,681,353), a portion of which can be conjugated to, for example,chondroitin sulfate, and the like.

The method of the invention is preferably implemented using thearticular cartilage instrument set 10 illustrated in FIGS. 1 and 2. Theset 10 includes a coring device 12 and a first obturator and a secondobturator 16. The coring device 12 includes a cylindrical tube extendinga distance along a coring axis A between a distal end 20 and a proximalend 22. A set of cutting elements 23, or teeth, are disposed at thedistal end 12, and a gripper receiving is at the proximal end. A gripper26 extends transverse to the axis A1 near the proximal end. In theillustrated embodiment, the gripper is in the form of a cylindricalshell extending about the proximal end to tube 12 (but other forms maybe used) which permits a surgeon to grip the coring device 12 with hishand and reciprocally rotate that element about axis Al and apply anaxial force in the direction of axis A1.

The obturators 14 and 16 each include cylindrical rods extending along arespective one of obturator axes A2 and A3 between said distal ends 30,40 and proximal ends 32, 42 respectively. Each of the rods has a surfaceS14, S16 at its distal end which extends at least partially transverseto the respective axes A2 and A3. In the illustrated embodiment, thesurfaces S14, S16 are planar and perpendicular to axes A2, A3, but inother embodiments, different shapes may be used, e.g. convex, concave orirregular. The outer diameters OD14, OD16 of the rods are slightly lessthan the inner diameter ID of the tube of coring device 12 so that theobturator may be slidingly within the tube of device 12 with axes A2 andA3 being substantially coaxial with axis A1. Pusher sections P14, P16are positioned at the proximal ends of the rods of obturators 14 and 16,respectively. The pusher sections P14, P16 have outer diameters d2larger then ID of device 12. The pusher sections P14, P16 may haverounded ends to permit a surgeon to easily apply an axial force by hand,while gripping the gripper members 26.

The length L14 of obturator 14 is selected so that when its rod ispositioned all the way into the tube of device 10, i.e. with section P14adjacent to end 22 of tube 12 the distal end 30 of obturator 14 isdisplaced by distance X1 from the end 20 of device 12. The length L16 ofobturator 16 is selected so that when obturator 16 is fully positionedwithin device 12, i.e. with section P16 adjacent to end 22 of tube 12,the end 40 of obturator 16 is substantially at (or extends beyond) thedistal end 20 of device 12. Variations of the lengths L1 and L2 arewithin the scope of the invention. Other dimensions of the instrumentsare indicated by reference designators in FIG. 2. In the preferredembodiment:

L=20 cm

OD12=6 (or 11) mm

d1=20 mm

d2=20 mm

ID=4 (or 9) mm

ID2=5 (or 10) mm

X1=2 cm

L1=18 cm

L2=20 cm

FIGS. 3-7 illustrate the method of the invention, using a variant of theinstrument set of FIGS. 1 and 2. In that embodiment, the tube of coringdevice 10 has a constant outer diameter along its length. In one form,the inner surface of the tube 12 is "rifled", i.e. has one or morehelical grooves extending about the coring axis A1, near the distal endof device 12, to aid in keeping the harvested cartilage and cancellousbone in place. In another form, as illustrated in FIGS. 1 and 2, thatinner surface defines a larger diameter (ID2) region near the distal end20 than at other locations along its length.

In FIG. 3, the first step of articular cartilage transplantation isshown, demonstrating shaving of articular cartilage lesion. FIG. 4 showsmicrofracture preparation of the base of a chondral lesion prior toarticular cartilage grafting. FIG. 5 shows harvesting of articularcartilage with cancellous bone from the intercondylar notch. FIGS. 6 and7 show transplantation of the articular cartilage and cancellous bonegraft to the prepared chondral defect. In accordance with the invention,the harvested articular cartilage and cancellous bone is crushed andmixed before transplantation.

The articular cartilage paste of the present invention is formed of anosteocartilaginous tissue mixture including crushed and mixed articularcartilage and cancellous bone in an effective amount for enhancingformation of cartilage. An "effective" amount of paste, as used herein,means the total amount of paste sufficient to show a meaningful patientbenefit, i.e., to enhance the formation of cartilage in the vicinity ofthe graft. Further, the paste can include an effective amount ofcartilage-stimulating factor, as described above.

Those of skill in the art will recognize that the invention may beembodied in other specific forms without departing from the spirit oressential characteristics thereof. The presently described embodimentsare therefore to be considered in all respects as illustrative and notrestrictive, the scope of the invention being indicated by the appendedclaims rather than by the foregoing description, and all variations ofthe invention which are encompassed within the meaning and range ofequivalency of the claims are therefore intended to be embraced therein.

What is claimed is:
 1. An articular cartilage paste comprising:an osteocartilaginous tissue mixture for effecting in vivo cartilage formation, the osteocartilaiinous tissue mixture comprising crushed articular cartilage and cancellous bone, a cartilage-stimulating factor, wherein the cartilage-stimulating factor comprises a TGF-β growth factor in an amount ranging from about 0.1 ug/ml to about 1.0 ug/ml.
 2. An articular cartilage paste comprising:an osteocartilaginous tissue mixture for effecting in vivo cartilage formation, the osteocartilaginous tissue mixture comprising crushed articular cartilage and cancellous bone, a cartilage-stimulating factor, wherein the cartilage-stimulating factor is contained within a non-toxic, bioabsorbable carrier.
 3. An articular cartilage paste comprising:an osteocartilaginous tissue mixture for effecting in vivo cartilage formation, the osteocartilaginous tissue mixture comprising crushed articular cartilage and cancellous bone, further comprising:a plurality of cells.
 4. The articular cartilage paste of claim 3 wherein the cells comprise a plurality of undifferentiated mesenchymal stem cells.
 5. The articular cartilage paste of claim 3 wherein the cells comprise a plurality of cloned chondrocytes.
 6. An articular cartilage paste comprising:an osteocartilaginous tissue mixture for effecting in vivo cartilage formation, the osteocartilaginous tissue mixture comprising crushed articular cartilage and cancellous bone, further comprising:a biological glue.
 7. The articular cartilage paste of claim 6 wherein the biological glue is selected from the group consisting of fibrin glue, mussel glue, chondronectin, osteonectin, fibronectin, arginine-glycine-aspartic acid peptide, and combinations thereof. 